tbuckley/cabot-search huggingface dataset:
Abstract 5471: Integrating tumor-intrinsic and immunological factors to identify immunogenic breast cancers from a low-risk cohort; results from the randomized SweBCG91RT trial
Authors: Axel Stenmark Tullberg, Martin Sjöström, Emma Niméus, Fredrik Killander, Laura Chang, Felix Y. Feng, Corey W. Speers, Lori J. Pierce, Anokó Kovács, Dan Lundstedt, Erik Holmberg, Per Karlsson
Journal: Cancer Research (2023)

Abstract Purpose: The local immune infiltrate’s influence on tumor progression may be linked to tumor-intrinsic factors. This study aimed to investigate whether integrating immunological and tumor-intrinsic factors could identify patients who may be candidates for de-escalation of radiotherapy (RT).Experimental Design: The practice-changing SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT with sparse use of systemic therapy (95% without systemic therapy) and followed for a median time of 15.2 years. We developed two gene expression models to capture immunological activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could identify a subgroup where RT de-escalation is feasible. Results: The immunomodulatory model correlated with proliferation and was named Proliferative Index. The immunological model was enriched for T cell signatures and was named Immunescore. Increased Proliferative Index predicted an increased prognostic benefit from Immunescore (pinteraction=0.01). Combining the two models stratified patients who may be recommended an escalated RT (RT boost) by RT benefit and prognosis. Patients with a low predicted risk benefited from standard RT (HR: 0.28, CI 95% 0.09-0.85, p=0.025) and had a 5.4% 10-year incidence of ipsilateral breast tumor recurrence (IBTR) after radiation. In contrast, the group with a high predicted risk, characterized by rapidly proliferating tumors without an immune infiltrate, had a clinically meaningful high 10-year incidence of IBTR despite RT treatment (19.5% (CI 95% 12.2-30.3)). Conclusions: Integrating tumor-intrinsic and immunological factors may identify immunogenic tumors in early-stage breast cancer populations and identify patients for whom de-escalated RT may be appropriate. Patients with rapidly proliferating tumors and an immune infiltrate may be candidates for RT de-escalation. Citation Format: Axel Stenmark Tullberg, Martin Sjöström, Emma Niméus, Fredrik Killander, Laura Chang, Felix Y. Feng, Corey W. Speers, Lori J. Pierce, Anokó Kovács, Dan Lundstedt, Erik Holmberg, Per Karlsson. Integrating tumor-intrinsic and immunological factors to identify immunogenic breast cancers from a low-risk cohort; results from the randomized SweBCG91RT trial. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5471.
Abstract 1486: The regulatory mechanism of LncRNA CCAT1 via three-dimensional genome structure in colorectal cancer cells
Authors: Yuhki Yokoyama, Hirofumi Yamamoto
Journal: Cancer Research (2023)

Abstract Kruppel-like factor 5 (KLF5) belongs to zinc finger transcription factors and its expression is up-regulated in specific cancer types, such as gastrointestinal cancer and squamous carcinoma. It is reported that KLF5 is associated with the maintenance of stemness and essential for the integrity of intestinal epithelium and oncogenesis. Colon Cancer Associated Transcript 1 (CCAT1) is a long noncoding RNA that was initially found to be up-regulated in colorectal cancer (CRC), and studies have reported that high CCAT1 expression is associated with poor prognosis in CRC patients. In this study, we performed in vitro enChIP (engineered DNA-binding molecule-mediated chromatin immunoprecipitation)-sequencing to identify the KLF5 enhancer region which interacts with KLF5 promoter region. We successfully identified the KLF5 enhancer region in colorectal cancer cells and further found that KLF5 promoter region interacted with the transcription start site (TSS) region of CCAT1 gene, which is located at the different chromosome. Our results indicated that KLF5 protein participated in the core regulatory circuitry together with co-factors (BRD4, MED1, and RAD21), which contributes to construction of the three-dimensional genome structures consisting of KLF5 promoter, enhancer and CCAT1 TSS region. We also found that CCAT1 expression was highly correlated with KLF5 expression in CRC clinical samples and that KLF5 regulated CCAT1 expression. In conclusion, our data propose the mechanistic insight that KLF5 protein constructs the core regulatory circuitry with co-factors in the three-dimensional genome structure and coordinately regulates KLF5 and CCAT1 expression in CRC. Citation Format: Yuhki Yokoyama, Hirofumi Yamamoto. The regulatory mechanism of LncRNA CCAT1 via three-dimensional genome structure in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1486.
Abstract 2214: NEDD9 as a prognostic biomarker and its immune landscape in lung adenocarcinoma
Authors: Leen M. Al-Kraimeen, Yaqeen M. Al-Kraimeen
Journal: Cancer Research (2023)

Abstract Introduction: Lung adenocarcinoma (LUAD) is the deadliest cancer worldwide. Many efforts are made to search for new biomarkers to screen for immunotherapy candidates and predict the response. Neural Precursor Cell Expressed, developmentally down-Regulated 9 (NEDD9), is predominantly expressed in many cancer types but has not been studied yet in lung adenocarcinoma. Herein, we analyzed the association of NEDD9 with immune inhibitory components to understand its immune landscape in lung adenocarcinoma. Methods: Gene expression profiles were retrieved from The Cancer Genomic Atlas Lung Adenocarcinoma cohort (n = 567). We used TIMER 2.0 for immune inhibitory cell infiltrates analysis. Tumor mutational burden (TMB) was measured using the cBioPortal tool. The enrichment analysis of function and signaling pathways of DEGs in LUAD was done by gene ontology (GO) using Enrichr. Results: NEDD9 is differentially expressed in LUAD tissues (P &amp;lt; 0.00). High NEDD9 expression had better overall survival prognostic value in LUAD patients (HR: 0.66, 95% CI: 0.49 - 0.89, P = 0.0221) compared to low expression. NEDD9 expression was positively correlated with the infiltration of cancer-associated fibroblasts and macrophage M2 cells (spearman’s ρ = 0.257, P &amp;lt; 0.001, ρ = 0.266, P &amp;lt; 0.001, respectively), but negatively with myeloid-derived suppressor cells (MDSC) (ρ = -0.344, P &amp;lt; 0.001). Moreover, survival analysis based on NEDD9 expression and MDSC levels revealed a better OS group identified by low MDSC levels and low NEDD9 expression after adjustment for age, stage, and purity. In terms of immune checkpoint genes’ expression, NEDD9 expression was directly correlated with CTLA-4, PD-1, PD-L1, VSIR, and LAG-3 (ρ &amp;gt; 0.2, Q value &amp;lt; 0.05). TMB was inversely associated with NEDD9 expression (ρ = -0.1, P &amp;lt; 0.001). GO analysis showed that genes co-expressed with NEDD9 were mainly in the phagocytic vesicles and participated in biological processes of cellular response to interferon-gamma by molecular function such as cysteine-type endopeptidase activity involved in apoptotic signaling pathways. Conclusion: We found that NEDD9 expression is a useful biomarker of immunosuppression in LUAD patients and can predict the response to immunotherapy. Our results suggest that NEDD9 is a favorable prognostic biomarker, which could be explained by low MDSC. Further studies are needed for a better understanding of the NEDD9 value in LAUD. Citation Format: Leen M. Al-Kraimeen, Yaqeen M. Al-Kraimeen. NEDD9 as a prognostic biomarker and its immune landscape in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2214.
Abstract 547: Role of KDM4A in bladder cancer
Authors: Bailey O. Warren, Ammar Y. Abdelfattah, Alia Ghoneum, Freddie Salsbury, Neveen A. Said
Journal: Cancer Research (2023)

Abstract Bladder cancer (BCa) is the most common malignancy of the urinary system in the United States. Most patients present with non-muscle invasive bladder cancer (NMIBC) that is treated with bladder preserving approaches. However, recurrence is high with a 50% chance to progression into muscle invasive bladder cancer (MIBC). Patients with MI disease are treated with aggressive surgery and/or systemic chemo-radiation, and more recently immune- and targeted therapies. Patients with BCa require life-long surveillance with expensive imaging, and repeated treatment courses, making BCa one of the most expensive malignancies throughout the patients’ lifespan. BCa therapies have been stagnant for almost four decades until 2016 when new immune and targeted therapies were approved for patients with locally advanced, recurrent, or metastatic disease, with an overall response of 15-29%. Thus, better understanding of the pathobiology of BCa is needed to identify actionable targets and develop novel therapeutics. In this respect, we have identified histone lysine demethylase 4A (KDM4A), also known as Jumanji D2A (JMJD2A) as a BCa onco-protein. We found that the expression of nuclear KDM4A significantly correlated with disease stage in patients’ tumors and in tobacco carcinogen-induced murine bladder tumors. KDM4A transcript expression significantly increased in bladder tumors compared to normal in TCGA data and three independent publicly available datasets. Knockdown of KDM4A in BCa cell lines significantly inhibited their proliferation and invasiveness. Interestingly, KDM4A transcripts exhibited significant inverse correlation with BCa tumor suppressor SPARC in five independent datasets. In addition, using phenotypic screening and computational modeling, we found that KDM4A is a direct target of verteporfin, a potent inducer of SPARC expression in BCa cell lines. Mechanistically, knockdown of KDM4A in BCa cell lines increased SPARC expression, whereas its overexpression inhibited basal and verteporfin-induced SPARC expression. Chromatin immune-precipitation (ChIP) assays indicated that verteporfin significantly inhibited the association of KDM4A with SPARC promoter. Together, our data underscore the oncogenic role of KDM4A in BCa and its potential as an actionable target. Citation Format: Bailey O. Warren, Ammar Y. Abdelfattah, Alia Ghoneum, Freddie Salsbury, Neveen A. Said. Role of KDM4A in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 547.
Abstract 1866: D02, a novel, non-blocking antibody targeting IL2RA, exhibits significant anti-tumor activity in IL2RA-humanized mice
Authors: Shuzhen Cao, Wenjiao Zhang, Qingcong Lin
Journal: Cancer Research (2023)

Abstract Regulatory T cells, or Tregs, are a subset of CD4+ T cells that negatively regulate immune responses to promote their resolution and protect against autoimmunity. Infiltration of Tregs in the tumor microenvironment (TME), and a low ratio of effector T cells to Tregs, is frequently associated with tumor progression and poor prognosis. The alpha subunit of the IL-2 cytokine receptor (IL2RA), a component of the high-affinity IL-2 receptor along with the β and γ subunits (IL2Rβγ), is constitutively expressed on Tregs and transiently expressed on effector T cells. IL-2 is a key cytokine for effector T cell survival and cytolytic responses. We aimed to discover an IL2RA-targeting antibody capable of depleting Tregs but permitting IL-2 stimulation of effector T cells in the TME. We developed a fully human IgG1 antibody specific to IL2RA, D02, from our proprietary RenMab™ mice, which contain the entire human immunoglobulin variable domain. D02 binds both human and cynomolgus monkey IL2RA with high affinity without hindering IL2RA-IL-2 binding or inhibiting IL-2 signaling. To evaluate the safety and efficacy of D02 in vivo, we established a syngeneic mouse tumor model in IL2RA-humanized mice. We observed that D02 potently inhibited MC38 (colon adenocarcinoma) tumor growth at 10 mg/kg. Further studies will aim to characterize the effect of D02 on the ratio of effector T cells to Tregs in the TME. These data indicate that D02 is a novel, IL2RA-specific monoclonal antibody that uniquely exhibits significant anti-tumor activity in vivo while preserving IL-2 signaling to effector T cells. Citation Format: Shuzhen Cao, Wenjiao Zhang, Qingcong Lin. D02, a novel, non-blocking antibody targeting IL2RA, exhibits significant anti-tumor activity in IL2RA-humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1866.
Abstract 6450: Fatty acid intake as potential risk factor of colorectal cancer: A multicenter case control study in Iran
Authors: Monireh Sadat Seyyedsalehi, Paolo Boffetta, Kazem Zendehdel
Journal: Cancer Research (2023)

Abstract A higher risk of colorectal cancer (CRC) has been associated with high animal fat intake, but not vegetable fat. To date, limited data provides the quantification of the effect exerted by fatty acids (FAs) on CRC overall and by anatomical sub-sites. This study aims to look at associations between some FAs intakes [cholesterol, total fat, total saturated fatty acids (SFAs), total monounsaturated fatty acids (MUFAs), total polyunsaturated fatty acids (PUFAs), total trans fatty acids (TFAs), oleic acid, myristic acid, total ruminant (rTFAs) and industrial fatty acids (iTFAs), eliadic acid (EA), conjugated linoleic acid (CLA), and CRC risk in a large case-control study (IROPICAN) in Iran . We analyzed 865 CRC cases (434 in colon, 404 in rectum, and 27 with unknown subsite) and 3,206 controls from seven provinces of Iran. Detailed information was collected by trained interviewers using validated lifestyle and food frequency questionnaires (FFQ). The different types of total and individual FAs intake were categorized into quartiles of intake. The odds ratios (OR) and 95% confidence intervals (CI) for the association between CRC them were calculated using multivariate logistic regression models by adjusting for the potential confounders. Furthermore, analyses were stratified by age (under and over 50) and also, we repeated the analyses for CRC subsites. There was a statistically significant positive association between CRC and high intake (quartile 4) compared to the low intake (quartile) of dietary total fat (OR=1.77, 95% CI=1.32-2.38), cholesterol (OR=1.58, 95% CI=1.22-2.05), total TFAs (OR=1.31, 95% CI=1.02-1.68), TFAs (OR=1.73, 95% CI=1.12-2.68), EA(OR=2.69, 95% CI=1.46-4.93), and SM (OR=1.45, 95% CI=1.00-2.09), as well as an inverse association with high intake of dietary rTFAs (OR=0.60, 95% CI=0.39-0.93), CLAs (OR=0.34, 95% CI=0.19- 0.60). Stratified analyses by age indicated that there was a statistically significant association between CRC and total fat intake [OR =1.30, 95% CI =1.16-1.46, p=0.006 for the interaction], cholesterol intake [OR =1.22, 95% CI=1.11-1.35, p=0.019 for the interaction], and iTFA intake [OR =1.31, 95% CI=1.06-1.62, p=0.02 for the interaction] after 50 years old. The results of our study indicate that decreasing fat consumption, particularly from industrial and animal sources, may reduce the risk of CRC. Citation Format: Monireh Sadat Seyyedsalehi, Paolo Boffetta, Kazem Zendehdel. Fatty acid intake as potential risk factor of colorectal cancer: A multicenter case control study in Iran [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6450.
Abstract 4405: Tumor mutational burden, as a potential predictive marker for the efficacy of immunotherapy in advanced gastric cancer
Authors: Jaeyeon Jang, Youngkyung Jeon, Sun Young Jeong, Ye Ji Jung, Daeho Choi, Joohyun Hong, Jeeyun Lee, Won Ki Kang, Seung Tae Kim
Journal: Cancer Research (2023)

Abstract Background: The optimal value of tumor mutational burden (TMB) for predicting treatment response of immunotherapy in advanced gastric cancer (AGC) is still unclear. We aimed to establish the optimal cut-off value of TMB, and evaluate the efficacy of immunotherapy in AGC according to TMB and other markers. Method: From October 1, 2020, to July 27, 2021, at Samsung medical center in Korea, patients with AGC, who received pembrolizumab or nivolumab were included. TMB was measured by next-generation sequencing (NGS)-based assays, and PD-L1 is tested using immune-histochemical assay 22C3 pharmDx. Based on receiver operating characteristic analysis, the cut-point value of TMB was determined as the point where the Youden’s index is maximum. Result: A total of 53 patients were analyzed. The cut-off value of TMB for predicting the overall response of immune checkpoint inhibitors was defined as 13.31 mutations/megabase (mt/mb), with 56% of sensitivity and 95% of specificity. Under this definition of TMB, 7 patients were TMB-high group (≥13.31 mt/mb), while 46 patients were TMB-low group (&amp;lt;13.31 mt/mb). The overall response rate (ORR) had a statistically significant difference between TMB-low (8.7%, n=4/46) and TMB-high patients (71.4%, n=5/7; p=0.001). The progression-free survival (PFS) and overall survival (OS) for 53 patients were 1.93 months (95% CI, 1.600-2.268) and 4.26 months (95% CI, 2.992-5.532). The OS was longer in the TMB-high group with the median of 20.8 months (95% CI, 2.292-39.281) compared to the TMB-low group with the median of 3.31 months (95% CI, 1.604-5.019; p=0.049). The ORR of the patients whose PD-L1 CPS was 1 or above was not different from the patients whose PD-L1 CPS was lower than 1. Conclusion: In this study, the optimal value of TMB for predicting the objective response rate of immunotherapy in AGC was determined as 13.31 mt/mb. TMB-high (≥13.31 mt/mb) was associated with a better objective response rate, and TMB-high patients exhibited better overall survival. TMB has the potential for predicting therapeutic response to immunotherapy in advanced gastric cancer. Citation Format: Jaeyeon Jang, Youngkyung Jeon, Sun Young Jeong, Ye Ji Jung, Daeho Choi, Joohyun Hong, Jeeyun Lee, Won Ki Kang, Seung Tae Kim. Tumor mutational burden, as a potential predictive marker for the efficacy of immunotherapy in advanced gastric cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4405.
Abstract 321: Metformin enhances the efficacy of enzalutamide treatment in castration-resistant prostate cancer
Authors: Kendall Elizabeth Simpson, ZhuangZhuang Zhang, Qiongsi Zhang, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract Prostate cancer remains to be the most commonly diagnosed cancer among men in the United states with approximately 268,500 new cases a year. One of the first treatment options for men with prostate cancer is androgen deprivation therapy (ADT), however, recurrence and metastases after ADT remain an issue and are categorized as castration-resistant prostate cancer (CRPC). Enzalutamide, an FDA approved drug currently prescribed to patients with CRPC, inhibits androgen receptor (AR) nuclear translocation preventing the transcriptional activity of AR. This therapy typically only extends the survival of patients with CRPC and can lead to Enzalutamide-resistance over time accenting the importance of new therapy targets. Metformin, a commonly used FDA approved therapy for type 2 diabetes, has been recently investigated as potentially having anti-tumor effects in many cancer types. In this study, we use Enzalutamide and Metformin in combination to explore possible re-sensitization of Enzalutamide-resistant CRPC to Enzalutamide. Recently, we have tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in Enzalutamide-resistant CRPC. After treatment, we see a decrease in cell proliferation and viability as well as a synergistic effect of both Enzalutamide and Metformin in Enzalutamide-resistant CRPC. Following these results, we sought to explore how this combination treatment effected key signaling markers for EMT, WNT signaling, and TGFβ signaling as well as key signaling markers for prostate cancer such as AR and prostate specific antigen (PSA). Since Metformin inhibits Complex I of oxidative phosphorylation, we also tested this combinational treatment using seahorse analysis to determine the mitochondrial respiration. After initial testing, we will continue to move forward in testing the effects of this combination treatment in Enzalutamide-resistant CRPC as well as further elucidate the underlying mechanisms contributing to this phenotype. Citation Format: Kendall Elizabeth Simpson, ZhuangZhuang Zhang, Qiongsi Zhang, Xiaoqi Liu. Metformin enhances the efficacy of enzalutamide treatment in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 321.